Title

Author

Defense Date

1993

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Microbiology & Immunology

First Advisor

Francine Marciano-Cabral

Abstract

The genus Naegleria is composed of a distinct group of free-living amoeboﬂagellates that include both pathogenic and nonpathogenic species. N. fowleri, the only pathogenic species of Naegleria to be isolated from humans, is the etiological agent of primary amoebic meningoencephalitis, a rare but rapidly fatal disease of the central nervous system in humans and in laboratory animals. The mechanisms of pathogenicity and the determinants of virulence of N. fowleri are unknown. Both pathogenic and nonpathogenic Naegleria activate the alternative complement pathway, however pathogenic N. fowleri are complement-resistant and nonpathogenic N. gruberi are complement-sensitive. The ability to resist complement-mediated lysis may be an important determinant of virulence of N. fowleri. These studies demonstrate that pathogenic N. fowleri possess at least two mechanisms for resisting complement lysis. Pathogenic N. fowleri synthesize a surface associated protein which appears to possess structural as well as functional homology to the human complement regulatory glycoprotein, CD59. Also, other surface glycoproteins appear to play a role in regulating complement lysis either directly or by indirect inhibitory mechanisms. In addition to complement regulatory glycoproteins, pathogenic N. fowleri possess the ability to remove membrane deposited complement proteins, C5b-C9, from their cell surface by membrane vesiculation. The presence of complement regulatory proteins and the ability to vesiculate in response to serum complement, alone or in combination, serves to protect pathogenic N. fowleri from complement-mediated damage. Nonpathogenic N. gruberi do not appear to possess surface complement regulatory proteins or the ability to vesiculate in response to serum complement. Additional studies demonstrate that growth medium modulates complement resistance and virulence. More importantly, by using changes in growth medium, an in vitro model was developed for differentially expressing proteins associated with the complement-resistant state. The induction of these de novo synthesized proteins may serve as markers of virulence and complement resistance in pathogenic N. fowleri amoebae.

Comments

Scanned, with permission from the author, from the original print version, which resides in University Archives.